This is a competitive renewal application for a 17-year project studying the immunomodulating properties of cannabinoids. Since the last renewal, we have established that THC has the unique property of biasing the T helper immune response to Legionella pneumophila infection toward Th2 immunity. This drug effect involves both CBI and CB2 cannabinoid receptors. Recently, there has been great interest in the potential use of marijuana and related compounds as therapeutics for the treatment of AIDS, cancers, and chronic inflammatory diseases. Because of this, it is imperative to continue to define the cellular and molecular mechanisms of the T helper cell modulating action of these compounds. We hypothesize that THC, through cannabinoid receptor signaling, activates gene programs commensurate with Th2 immunity and suppresses programs for Thl immunity. This drug property might profoundly affect marijuana users but may also be potentially useful when harnessed in a therapeutic application. Aim 1 will define the cellular and molecular mechanisms responsible for the drug-induced decrease in It-12 and IL-12 receptor. It will also determine the potential Th2 biasing property of THC for other antigens such as those from HIV. Purified subpopulations of mouse immune cells will be studied as well as immune cells from CB? and CBI knockout mice. A murine vaccination model employing HIV antigen based DNA vaccines will also be used. Aim 2 will study dendritic cells (DCs) and cell lines in detail as a major cellular target of THC action. We will determine if these cells express CBRs and how the drug affects DC interaction with T helper cells, the handling of antigen by DCs, and the maturation and development of DCs. Aim 3 will determine the involvement of a number of CBR-linked and Th-linked signaling pathways in the drug-induced modulation of Thl and Th2 immunity. We will determine the role of transcription factors such as GATA3, NF-kB, AP-1, CREB, and STAT4, as well as other signaling proteins such as MAPK. We have preliminary evidence that these interrelated factors are modulated through CBR ligation and therefore are at the core of drug-induced modulation of T helper immunity. These results will define the molecular and cellular mechanisms of cannabinoid effects on T helper immunity and will increase our understanding of the potential public health risks and benefits of marijuana use.